Metastatic prostate cancer - Treatment

By definition, locally advanced and metastatic prostate cancer is not amenable to radical treatment. Historically, most patients were presented with this form of the disease. However, with the advent of the PSA screening era, the situation has changed for the better. However, despite this, there are still many men in the world who are diagnosed with the disease at a late stage.

Locally advanced prostate cancer means that it has spread beyond the capsule without distant metastases or regional lymph node metastases. Metastatic prostate cancer means lymph node metastases, bone metastases, or soft tissue metastases.

The main method of treatment for patients with locally advanced and metastatic forms of prostate cancer is hormonal therapy.

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Hormonal treatment for prostate cancer

The effectiveness of hormonal treatment (surgical castration and estrogen administration) in patients with metastatic prostate cancer was first demonstrated in 1941.

Since then, hormonal therapy has been one of the main methods of treating patients with advanced forms of prostate cancer. Currently, the use of hormonal therapy is not limited to a group of patients with metastatic forms of the disease; its use as monotherapy or as part of multimodal treatment is also being discussed for non-metastatic prostate cancer.

Molecular Basis of Hormonal Control of the Prostate

Growth, functional activity and proliferation of prostate cells are possible with adequate stimulation by androgens. The main androgen circulating in the blood is testosterone. Although it does not have oncogenic properties, it is necessary for the growth of tumor cells.

The main source of androgens in the male body are the testicles, about 5-10% of androgens are synthesized by the adrenal glands. More than half of the testosterone in the blood is bound to the sex hormone, about 40% to albumin. The functionally active, unbound form of testosterone is only 3%.

After passive diffusion through the cell membrane, testosterone is converted into dihydrotestosterone by the enzyme 5-a-reductase. Although the physiological effects of testosterone and dihydrotestosterone are similar, the latter is 13 times more active. The biological effect of both substances is realized by binding to androgen receptors located in the cytoplasm of cells. Subsequently, the ligand-receptor complex moves to the cell nucleus, where it attaches to specific promoter zones of genes.

Testosterone secretion is under the regulatory influence of the hypothalamic-pituitary-gonadal axis. LHRH secreted by the hypothalamus stimulates the secretion of LH and FSH in the anterior pituitary gland. The action of LH is aimed at stimulating the secretion of testosterone by the interstitial Leydig cells in the testes.

Negative feedback with the hypothalamus is provided by androgens and estrogens circulating in the blood, formed from androgens as a result of biotransformation.

Regulation of androgen synthesis in the adrenal glands occurs through the axis "hypothalamus (corticotropin-releasing factor) pituitary gland (adrenocorticotropic hormone) - adrenal glands (androgens)" by a feedback mechanism. Almost all androgens secreted by the adrenal glands are in an albumin-bound state, their functional activity is extremely low compared to testosterone and dihydrotestosterone. The level of androgens secreted by the adrenal glands remains at the same level after bilateral orchiectomy.

Androgen deprivation of prostate cells ends with their apoptosis (programmed cell death).

Creation of androgen blockade

Currently, two main principles are used to create androgen blockade:

• suppression of androgen secretion by the testicles through medical or surgical castration;
• inhibition of the action of androgens circulating in the blood at the level of receptor interaction in prostate cells (antiandrogens).

The combination of these two principles is reflected in the concept of “maximum (or complete) androgen blockade”

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Decreased blood testosterone levels (castration)

Bilateral orchiectomy

Bilateral orchiectomy leads to a decrease in testosterone levels to less than 50 ng/dl in a short period of time (based on the results of the operations, this level is considered castration). 24 hours after surgical castration, the testosterone concentration decreases by 90%. Given this, bilateral orchiectomy is considered the "gold" standard for creating androgen blockade, the effectiveness of all other methods is assessed in comparison with this operation.

This operation can be performed on an outpatient basis under local anesthesia using one of two methods: total orchiectomy or subcapsular orchiectomy with preservation of the epididymis and visceral layer of the vaginal membrane. Subcapsular orchiectomy allows patients to avoid the negative psychological impact of an "empty" scrotum, but requires the attention of a urologist to completely remove intratesticular tissue containing Leydig cells. If the operation is technically performed correctly, the results of propoi and subcapsular orchiectomy are identical.

Recently, a decrease in the prevalence of surgical castration can be noted, associated with the diatonic nature of the disease in early stages, as well as the use of pharmacological treatment methods equivalent in effectiveness to castration.

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Estrogens

Estrogens have a multicomponent mechanism of action:

• decrease in LHRH secretion due to the feedback mechanism:
• androgen inactivation;
• direct inhibition of Leydig cell function:
• direct cytotoxic effect on prostatic epithelium (proven only in vitro).

The most commonly used estrogen is diethylstilbestrol. The use of estrogens is limited due to the high level of cardiotoxicity and the risk of vascular complications (thrombogenic properties of estrogen metabolites) even at low doses (1 mg), despite the effectiveness comparable to surgical castration.

Currently, interest in estrogen therapy is based on three positions.

• Compared to LHRH receptor agonists, estrogens are less expensive and do not cause dangerous side effects (osteoporosis, cognitive impairment).
• Estrogens are highly effective in patients with androgen-refractory prostate cancer.
• New beta class estrogen receptors have now been discovered, which are presumably related to prostate oncogenesis.

To prevent cardiovascular toxicity of estrogens, it is proposed to use the parenteral route of drug administration (to exclude the formation of toxic metabolites due to the first-pass effect through the liver), as well as cardioprotective drugs. However, studies have shown that the use of anticoagulants and antiplatelet agents based on their angioprotective effect does not actually reduce the risk of thromboembolic complications.

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Hormone releasing inhibitors

Releasing hormone receptor agonists (LHRH) (buserelin, goserelin, leuprorelin, triptorelin) are synthetic analogues of LHRH. Their mechanism of action consists of initial stimulation of pituitary LHRH receptors and secretion of LH and FSH, which increase testosterone production by Leydig cells. After 2-4 weeks, the feedback mechanism suppresses the synthesis of pituitary LH and FSH, which leads to a decrease in blood testosterone levels to castration levels. However, the use of LHRH receptor agonists does not achieve this in approximately 10% of cases.

A meta-analysis of 24 large studies including approximately 6,600 patients found that survival in patients with prostate cancer treated with LHRH receptor agonists alone was no different from that in patients who had undergone bilateral orchiectomy.

The initial "flare" of LH concentration, and accordingly testosterone in the blood, begins 2-3 days after the injection of these drugs and lasts up to 10-20 days. Such a "flare" can lead to a life-threatening exacerbation of the symptoms of the disease, especially in patients with its widespread forms. Among such symptoms should be listed bone pain, acute urinary retention, renal failure due to obstruction of the ureters, compression of the spinal cord, serious complications from the cardiovascular system due to the tendency to hypercoagulation. There are differences between the phenomena of "clinical flare" and "biochemical flare" (increased PSA levels). Patients with a large volume of bone tissue damage, which is symptomatic (about 4-10% of patients with stage M1 disease), are most susceptible to the phenomenon of "clinical flare".

When using LHRH receptor agonists, it is necessary to simultaneously prescribe antiandrogenic drugs, which prevents the described undesirable effects of increased testosterone levels. Antiandrogens are used for 21-28 days.

For patients with a high risk of spinal cord compression, it is necessary to use agents that lead to a rapid decrease in blood testosterone levels (surgical castration, LHRH antagonists).

Releasing hormone receptor antagonists

Administration of LHRH receptor antagonists (cetrorelix) results in a rapid decrease in testosterone levels due to blockade of LHRH receptors in the pituitary gland: within 24 hours after administration, the concentration of LH decreases to 84%. Given this, there is no need to administer antiandrogen drugs due to the absence of the “flare” phenomenon.

The efficacy of monotherapy with LHRH antagonists is comparable to that of LHRH agonists administered in combination with antiandrogens.

The possibility of widespread use of drugs in this group is complicated by a number of facts. Most LHRH receptor antagonists are capable of causing serious histamine-mediated allergic reactions, including after previous successful administration. Given this, these drugs are prescribed to patients who have refused surgical castration, for whom other drug options for hormonal treatment are impossible.

Medical staff monitor the patient for 30 minutes after administration of the drug due to the high risk of allergic reactions.

Androgen synthesis inhibitors

Ketoconazole is an oral antifungal drug that inhibits the synthesis of androgens by the adrenal glands and testosterone by Leydig cells. The effect after administration of the drug occurs very quickly, sometimes within 4 hours after administration: the effect of ketoconazole is also quickly reversible, so a constant (400 mg every 8 hours) dosing regimen is necessary to maintain testosterone at a low level.

Ketoconazole is a fairly well-tolerated and effective drug; it is prescribed to patients for whom first-line hormonal treatment has proven ineffective.

Despite the rapidly developing effect, long-term treatment with ketoconazole in patients without concomitant hormonal modulation (surgical, drug castration) leads to a gradual increase in blood testosterone levels to normal values within 5 months.

Currently, the use of ketoconazole is limited to a group of patients with androgen-refractory prostate cancer.
Side effects of ketoconazole treatment include gynecomastia, lethargy, general weakness, liver dysfunction, visual impairment, and nausea.
Given the suppression of adrenal function, ketoconazole is usually prescribed in combination with hydrocortisone (20 mg 2 times daily).

Antiandrogen treatment

Antiandrogens block intracellular receptors with greater affinity than testosterone, thereby causing apoptosis of prostate cells.

Orally administered antiandrogens fall into two main groups:

• antiandrogens with a steroid structure (cyproterone, medroxyprogesterone);
• nonsteroidal antiandrogens (flutamide, bicalutamide, nilutamide).

Steroid antiandrogens also have a suppressive effect on the pituitary gland, due to which the testosterone level decreases, whereas with the use of non-steroidal drugs the testosterone level remains normal or slightly elevated.

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Steroidal antiandrogens

Cyproterone is one of the first and most well-known drugs in the group of antiandrogens with direct blocking action on androgen receptors, also reducing the concentration of testosterone in the blood due to central suppression (progestogenic properties). Cyproterone is taken orally, the recommended dose is 100 mg 2-3 times a day.

In monotherapy, the efficacy of cyproterone is comparable to flutamide.

Side effects of cyproterone are caused by hypogonadism (decreased libido, impotence, increased fatigue), up to 10% of patients may experience severe complications from the cardiovascular system, which limits the use of this drug. Gynecomastia is a side effect in less than 20% of men taking cyproterone. The literature mentions rare observations of fulminant hepatotoxicity.

Nonsteroidal antiandrogens ("pure" antiandrogens)

Blocking androgen receptors with antiandrogens increases the concentration of LH and testosterone by approximately 1.5 times due to the mechanism of positive feedback with the hypothalamus. The absence of a decrease in testosterone levels allows avoiding a number of side effects caused by hypogonadism: loss of libido, poor health, osteoporosis.

Despite the fact that a direct comparison of the three drugs used (bicalutamide, flutamide, nilutamide) in monotherapy was not conducted, they are practically the same in the severity of pharmacological side effects: gynecomastia, mastodynia, hot flashes. However, bcalutamil is somewhat safer compared to nilutamide and flutamide.

Gynecomastia, mastodynia, hot flashes are caused by peripheral aromatization of excess testosterone to estradiol.
Gastrointestinal toxicity (primarily diarrhea) is more common in patients taking flutamil. All antiandrogens are hepatotoxic to varying degrees (from mild to fulminant forms), and therefore periodic monitoring of liver function is necessary.

Despite the fact that the mechanism of action of "pure" antiandrogens does not involve a decrease in testosterone levels, long-term preservation of erectile function is possible only in every fifth patient.

Nilutamide: There are currently no studies regarding the use of this drug as monotherapy for prostate cancer in comparison with other antiandrogens or castration.

Recent studies of the use of nilutamide as a second-line drug for the treatment of patients with androgen-refractory prostate cancer have shown a good response to therapy.

Non-pharmacological side effects of nilutamide include visual impairment (prolonged adaptation to darkness after bright light - about 25% of patients), interstitial pneumonia (up to pulmonary fibrosis) is possible in 1% of patients, hepatotoxicity, nausea, and sensitization to alcohol.

The half-life of nilutamide is 56 hours. Elimination occurs with the participation of the cytochrome P450 system of the liver. The recommended dosage of the drug is 300 mg once a day for 1 month, then a maintenance dose of 150 mg once a day.

Flutamide is the first drug from the family of "pure" antiandrogens. Flutamide is a prodrug. The half-life of the active metabolite, 2-hydroxyflutamide, is 5-6 hours, which necessitates a 3-times daily dosing regimen (250 mg 3 times a day). 2-hydroxyflutamide is excreted by the kidneys. Unlike steroid antiandrogens, there are no side effects due to fluid retention or thromboembolic complications.

The use of flutamide as monotherapy compared with orchiectomy and maximum androgen blockade does not affect survival in patients with advanced prostate cancer.

Non-pharmacological side effects - diarrhea, hepatotoxicity (rarely - fulminant forms).

Bicalutamide is a nonsteroidal antiandrogen with a long half-life (6 days). Bicalutamide is prescribed once a day and is characterized by high compliance.

Bicalutamide has the highest activity and the best safety profile among "pure" antiandrogens. The pharmacokinetics of the drug are not affected by age, mild to moderate renal and hepatic insufficiency.

In most patients, the blood testosterone level remains unchanged. The use of bicalutamide at a dose of 150 mg in patients with locally advanced and metastatic forms of the disease is comparable in effectiveness to surgical or medical castration. At the same time, it has much better tolerance in terms of sexual and physical activity. However, the incidence of gynecomastia (66.2%) and mastodynia (72.8%) in this group of patients is high.

Bicalutamide is not recommended for patients with limited disease because it is associated with decreased life expectancy.

After the administration of drugs that cause androgen deprivation, the effect is more or less obvious in most patients. Given that the target for hormonal treatment is androgen-sensitive prostate cells, an incomplete or erased effect indicates the presence of a population of androgen-refractory cells. PSA as a biological marker has a certain predictive ability regarding the response to hormonal treatment. For example, in patients with a PSA decrease dynamics of more than 80% after 1 month of hormonal therapy, life expectancy is significantly longer. Such indicators as PSA nadir and testosterone levels before treatment also have predictive ability.

The probability of transition to androgen-refractory prostate cancer within 24 months is 15 times higher in patients whose PSA level has not reached undetectable values in the blood during hormonal treatment. An increase in the Gleason sum by 1 point increases the probability of developing androgen-refractory cancer by 70%.

When calculating the probability of disease progression, it is necessary to take into account the dynamics of the growth of the PSA level before the start of treatment and the decrease in the level during hormonal treatment. A rapid increase in the PSA level before the start of treatment and its slow decrease are prognostically unfavorable factors in relation to the life expectancy of patients.

Almost all patients without exception who are clinically no longer responsive to hormonal treatment (transition to androgen-refractory prostate cancer) need to be in a state of androgen blockade, since remaining refractory to the absence of androgens, prostate cells are sensitive to them. According to some authors, predictors of life expectancy in this group of patients are the general somatic status, the activity of LDH and alkaline phosphatase in the blood serum, the hemoglobin level and the severity of the response to second-line treatment. Also predictors are a 50% decrease in the PSA level during chemotherapy, the presence or absence of diseases of the internal organs, the initial PSA level.

Combined hormonal treatment

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Minimal androgen blockade (peripheral androgen blockade)

It involves the simultaneous use of a 5-a-reductase inhibitor and a non-steroidal antiandrogen drug. The advantages of this treatment regimen are maintaining quality of life and sexual function at an acceptable level.

Until final results of clinical trials are obtained, the use of this treatment regimen is not recommended.

Maximum androgen blockade

Considering that after surgical or medical castration a certain low level of androgens secreted by the adrenal glands is maintained in the blood, the concept of maximum androgen blockade (a combination of castration and antiandrogens) is interesting.

However, the clinical benefit of such a treatment regimen is questionable in everyday clinical practice.

Systematic reviews and meta-analyses of recently completed large-scale studies have shown that 5-year survival of patients treated with maximum androgen blockade is less than 5% higher than that of patients treated with monotherapy (castration).

The use of maximum androgen blockade in patients with advanced forms of prostate cancer is associated with a high frequency and severity of side effects, as well as a significant increase in the cost of treatment.

Continuous or intermittent hormonal treatment

After some time from initiation of androgen deprivation treatment, prostate cancer cells become androgen-refractory: the absence of androgens no longer triggers apoptosis for certain cell lines.

The concept of intermittent hormonal therapy is based on the assumption that when hormonal therapy is discontinued, further tumor development occurs due to differentiation of the androgen-sensitive cell line. Thus, allowing the phenomenon of androgen withdrawal to be used repeatedly. This is why the transition of prostate cancer to androgen-refractory can be delayed in time.

In addition, intermittent hormonal treatment can improve the quality of life of patients between treatment cycles and reduce treatment costs.

The equivalence of intermittent and continuous approaches in the treatment of patients with metastatic prostate cancer, as well as relapse after radical treatment, has been confirmed by a number of clinical studies.

In one study, the PSA nadir achieved after 9 months of introductory hormonal treatment served as an independent prognostic factor for patient survival. A decrease in PSA levels after the introductory treatment cycle of less than 0.2 ng/mL, less than 4 ng/mL, or more than 4 ng/mL corresponded to a median survival of 75 months, 44 months, and 13 months, respectively, in patients with advanced prostate cancer.

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Immediate or delayed hormonal treatment

There is currently no clear opinion regarding the time of initiation of hormonal treatment. Previously proposed regimens suggest the possibility of starting therapy both immediately after the failure of radical treatment and after the appearance of clinical signs of metastasis.

This situation is associated with the lack of possibility to extrapolate the results of clinical studies due to their limitations into everyday practice.

The course of prostate cancer and the use of hormonal treatment are characterized by a number of facts.

Firstly, even in men who are hormonally intact, prostate cancer progresses over a long period of time. Studies show that after a relapse of prostate cancer, it takes 8 years for metastasis to occur. Another 5 years from the moment of metastasis until the patient's death.

Secondly, in 20% of men undergoing hormonal treatment for prostate cancer, the cause of death will not be related to this disease, while in the rest, the cause of death is the transition of cancer to a hormone-refractory form. One of the prospective randomized studies shows that 10 years after the start of hormonal treatment, only 7% of the group of patients remained alive. The average life expectancy after the start of hormonal therapy is 4.4 years, after 8 years, about 4.5% of patients remain alive.

Third, hormonal treatment is not harmless. Regardless of the side effects of the therapy, men who receive hormonal treatment for prostate cancer age much faster, leading to early death from age-related causes.

Therefore, a rational approach to the timing of initiation of hormonal treatment in patients with prostate cancer is needed.

There is currently a very clear position regarding hormonal treatment in patients with localized prostate cancer. The life expectancy of this group of patients under hormonal therapy is significantly lower than that under a delayed treatment strategy. This is due to the fact that the appointment of hormonal treatment leads to rapid aging of those patients whose risk of death from prostate cancer is already low.

In such a situation, the appointment of hormonal treatment should be discussed in detail with the patient.

Prostate cancer with metastases to regional lymph nodes

The results of immediate and delayed treatment with hormonal drugs in patients with stage pN1-3 disease (histological examination after RP) were assessed by a group of researchers from the Eastern Cooperative Oncology Group (ECOG) and the European Organization for Research and Treatment of Bladder Cancer.

The first study showed that after 7.1 years of follow-up, mortality was higher in the deferred treatment group than in the immediate hormonal therapy group. A subsequent update of this study showed that the median survival was 13.9 years in the immediate treatment group versus 11.3 years in the deferred treatment group. Despite the high non-prostate cancer mortality rate (55% versus 11% in the deferred treatment group), immediate hormonal therapy had a clear clinical advantage.

However, the clear interpretation and objectivity of the results of this study are limited due to the small group of patients studied (100 men), the lack of calculation of the correlation between life expectancy and the degree of differentiation of tumor cells, and the absence of a group of patients who received only hormonal treatment.

A study by the European Organisation for Research and Treatment of Bladder Cancer group (302 patients with stage pN1-3.M0 disease without primary treatment of the primary lesion) showed that the average survival time of patients who received hormonal treatment immediately after diagnosis was 7.8 years compared with 6.2 years in the group of patients with delayed therapy.

Locally advanced and asymptomatic metastatic prostate cancer

One of the studies by the Medical Research Council Prostate Cancer Working Party Investigators Group (934 patients), started back in 1997 (the results were assessed in 2004), showed that for patients in this group, immediate administration of hormonal treatment has a positive effect on both cancer-specific survival time and the severity of symptoms associated with prostate cancer. However, against the background of long-term observation of patients, the overall survival time did not change significantly depending on the time of initiation of hormonal treatment.

Conclusions

• Hormonal treatment should not be used in men with localized prostate cancer because it does not improve overall survival and only worsens mortality from other causes.
• For patients with locally advanced, asymptomatic metastatic, and symptomatic but not staged prostate cancer, the use of immediate hormonal treatment results in a significant increase in cancer-specific survival without affecting overall survival.
• In patients with stage N+ prostate cancer after RP, the average survival time is significantly longer with immediate hormonal treatment; for patients without primary treatment, the increase in survival time is not significant.

Follow-up of patients with prostate cancer receiving hormonal treatment

• Patients are examined at 3 and 6 months after the start of treatment. The minimum scope of examination is determination of the PSA level, digital rectal examination and a thorough assessment of symptoms aimed at obtaining evidence of the effectiveness of treatment and its side effects.
• The patient is monitored on an individual basis, taking into account symptoms, prognostic factors and prescribed treatment.
• Patients with stage M0 disease who have responded well to treatment are examined (symptom assessment, digital rectal examination, PSA determination) every 6 months.
• Patients with stage M1 disease who have responded well to treatment are assessed (symptom assessment, digital rectal examination, PSA determination, complete blood count, creatinine, alkaline phosphatase) every 3-6 months.
• In cases where there are signs of disease progression or poor response to treatment, an individual approach to monitoring is necessary.
• Routine use of instrumental examination methods (ultrasound, MRI, CT, osteoscintigraphy) in a stable patient’s condition is not recommended.

Complications of hormonal treatment for prostate cancer

Side effects of hormonal treatment for patients with prostate cancer have been known for a long time (Table 33-19). Some of them negatively affect the quality of life of patients, especially young people, while others can significantly increase the risk of health problems associated with age-related changes.

Side effects of hormonal treatment

Castration
Side effects	Treatment/prevention
Decreased libido	No
Impotence	Phosphodiesterase-5 inhibitors, intracavernous injections, local negative pressure therapy
Hot flashes (55-80% of patients)	Cyproterone, clonidine. venlafaxine
Gynecomastia, mastodynia (50% maximum androgen blockade, 10-20% castration)	Prophylactic radiation therapy, mammectomy, tamoxifen, aromatase inhibitors
Weight gain	Physical exercise
Muscle weakness	Physical exercise
Anemia (severe in 13% of patients with maximal androgen blockade)	Erythropoietin preparations
Osteopenia	Exercise, calcium and vitamin D supplements, bisphosphonate
Cognitive disorders	No
Cardiovascular pathology (myocardial infarction, heart failure, stroke, deep vein thrombosis, pulmonary embolism)	Parenteral administration, anticoagulants
Antiandrogens
Steroids
Pharmacological side effects: decreased libido, impotence, rarely gynecomastia
Non-pharmacological
Non-steroidal
Pharmacological side effects: mastodynia (40-72%), hot flashes (9-13%), gynecomastia (49-66%)	Prophylactic radiation therapy, mammectomy, tamoxifen, aromatase inhibitors
Non-pharmacological

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Osteoporosis

The risk of bone fractures in the group of patients receiving hormonal treatment for prostate cancer is significantly higher than in the general population. Hormonal treatment for 5 years increases the risk of fractures by 1.5 times, and for 15 years, by more than 2 times.

Diagnosis of osteoporosis involves performing X-ray absorptiometry to determine the bone density of the femur, which is performed in all men who are planned for hormonal treatment.

Regular exercise, quitting smoking, and taking calcium and vitamin D supplements can help increase mineral density. Bisphosphonates (preferably zoledronic acid) should be prescribed to all men with confirmed osteoporosis to prevent osteoporosis.

Hot flashes

Hot flashes are a subjective sensation of heat in the upper body and head, objectively accompanied by increased sweating.

Presumably, the cause of this complication is an increase in the tone of adrenergic centers in the hypothalamus, pathological deviations in the concentration of beta-endorphins, and the influence of peptides associated with the calcitonin gene on the thermoregulatory centers of the hypothalamus.

Treatment of hot flashes should only be performed in patients who are intolerant to this side effect of hormonal treatment.

Cyproterone (initial dose 50 mg/day, then titrated to 300 mg/day) significantly reduces the frequency of hot flashes due to its progestogenic effect.

The use of estrogens (minimal dose diethylstilbestrol or transdermal estradiol) is most effective (more than 90% effective). However, severe mastodynia and thromboembolic complications due to estrogen administration usually limit their use.

Antidepressants (especially selective serotonin reuptake inhibitors, venlafaxine) reduce the frequency of hot flashes by 50%.

Sexual function

About 20% of patients receiving hormonal treatment retain some degree of sexual function. Libido is more negatively affected. Only about 5% of patients retain a high level of sexual interest.

In a certain group of patients, oral phosphodiesterase type 5 inhibitors and intracavernous injections of alprostadil are effective.

Gynecomastia

Gynecomastia is caused by excess estrogen in the body (estrogen therapy, peripheral transformation of androgens into estrogens during treatment with antiandrogen drugs); up to 66% of patients taking bicalutamide at a dose of 150 mg. detect gynecomastia, of which up to 72% report pain in the mammary glands.

To prevent or eliminate painful gynecomastia, the possibility of using radiation therapy (10 Gy) was investigated, which is ineffective if gynecomastia has already manifested itself. Liposuction and mastectomy are also used to treat this complication. Tamoxifen is used to reduce the severity of mastodynia.

Anemia

Normochromic, normocytic anemia is found in 90% of patients receiving hormonal treatment for prostate cancer. As a rule, a decrease in hemoglobin content of about 10% is noted. The hemoglobin concentration decreases after 1 month in most men (87%) and returns to baseline values after 24 months due to compensatory mechanisms.

For the treatment of anemia, regardless of the etiology, recombinant erythropoietin preparations are used. Anemia is reversible after discontinuation of hormonal therapy within a year.

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